High-density lipoprotein coated medical devices

ABSTRACT

Method are disclosed for local and systemic administration HDL, recombinant HDL or HDLm for the prevention, treatment, or amelioration of a vascular disorder, disease or occlusion such as restenosis or vulnerable plaque.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of U.S. patent application Ser. No.11/027,822, filed on Dec. 29, 2004, and issuing as U.S. Pat. No.7,959,659, B2 on Jun. 14, 2011, which is a continuation-in-part of U.S.patent application Ser. No. 11/001,225 filed on Nov. 30, 2004, and nowabandoned. Priority is also claimed to U.S. Provisional application Ser.No. 60/534,045, filed Jan. 2, 2004, the teachings of which areincorporated herein.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention generally relates to methods of local and systemicadministration of a high-density lipoprotein (HDL) for the prevention,treatment, or amelioration of a vascular disorder, disease or occlusionsuch as restenosis or vulnerable plaque. The invention also relates HDLcoated stents or stents including HDL.

2. Description of the Background

Cholesterol is a soft, waxy substance found among the lipids (fats) inthe bloodstream and in all body's cells. It is an important part of ahealthy body because it is used to form cell membranes, some hormonesand is needed for other functions. But a high level of cholesterol inthe blood—hypercholesterolemia—is a major risk factor for coronary heartdisease, which leads to heart attack.

High blood cholesterol is one of the major risk factors for heartdisease. A risk factor is a condition that increases one's chance ofgetting a disease. In fact, the higher one's blood cholesterol level,the greater one's risk for developing heart disease or having a heartattack. Heart disease is the number one killer of women and men in theUnited States. Each year, more than a million Americans have heartattacks, and about a half million people die from heart disease.

Cholesterol and other fats cannot dissolve in the blood. Cholesterolshave to be transported to and from the cells by special carriers calledlipoproteins. There are several kinds, but the ones to focus on arelow-density lipoprotein (LDL) and high-density lipoprotein (HDL).

Low-density lipoprotein is the major cholesterol carrier in the blood.If too much LDL cholesterol circulates in the blood, it can slowly buildup in the walls of the arteries feeding the heart and brain. Togetherwith other substances it can form plaque, a thick, hard deposit that canclog arteries. This condition is known as atherosclerosis. A clot(thrombus) that forms near this plaque can block the blood flow to partof the heart muscle and cause a heart attack. If a clot blocks the bloodflow to part of the brain, a stroke results. A high level of LDLcholesterol reflects an increased risk of heart disease. Lower levels ofLDL cholesterol reflect a lower risk of heart disease.

About one-third to one-fourth of blood cholesterol is carried by HDL. Ithas been documented that HDL tends to carry cholesterol away from thearteries and back to the liver, where it is passed from the body or, inthe alternative, removes excess cholesterol from plaques and thus slowstheir growth. A low HDL level indicates a greater risk. A low HDLcholesterol level also may raise stroke risk.

It has been reported the level of serum HDL is inversely associated withthe plaque size in coronary arteries (see, for example, von Bergrelen,et al., Circulation 108(22):2757-62 (2003)). U.S. Pat. Nos. 5,746,223and 6,367,479 to Williams, for example, describe methods for increasingserum HDL level using a composition comprising large unilamellarvesicles or small unilamellar vesicles.

Steven Nissen et al., reported in November 2003 (JAMA 2003; 290:2292-2300) that in a double-blind, randomized, placebo-controlledmulticenter pilot trial, five weeks of infusion of an HDL-mimic,recombinant ApoA-I Milano/phospholipid complex could reduce 4% volume ofplaque in patients with prior heart attacks. This study showed systemicdelivery of HDL or HDLm may be a promising therapy to reduce plaque.

Nonetheless, there is no report on a method drawn to increase the locallevel of HDL at the plaque site. Nor is there any report on a method ofcontrolled release of HDL at the plaque site.

The methods and device disclosed herein address the above describedproblems and needs.

SUMMARY OF THE INVENTION

Provided herein is a method of using an implantable device forcontrolled release of an apolipoprotein. In some embodiments, theimplantable device can be a stent that includes a coating having anapolipoprotein such as HDL, recombinant HDL, HDLm or a combinationthereof for release of the apolipoprotein. In some other embodiments,the implantable device can be a bioabsorbable device (e.g., abioabsorbable stent) that carries or includes the apolipoprotein. Thebioabsorbable device can be made of a biocompatible polymer and/or anabsorbable metal. The coating or the bioabsorbable device can be capableof providing a controlled release profile, such as fast release,sustained release, intermediate release, or a combination thereof, ofthe apolipoprotein. The coating or the bioabsorbable device mayoptionally include a biobeneficial material and/or a bioactive agent.Some exemplary bioactive agents are paclitaxel, docetaxel, estradiol,nitric oxide donors, super oxide dismutases, super oxide dismutasesmimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),tacrolimus, dexamethasone, rapamycin, rapamycin derivatives,40-O-(2-hydroxy)ethyl-rapamycin (everolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin,ABT-578, clobetasol, prodrugs thereof, co-drugs thereof, and acombination thereof.

The HDL, recombinant HDL, HDLm and/or optionally one or more additionalagents can be coated onto the device free of a polymer or in combinationwith a biocompatible polymer. The biocompatible polymer can be ahydrophobic polymer, which can be durable or bioabsorbable. Thebiocompatible polymer also can be a biobeneficial material, ahydrophilic polymer or a polymer having at least one hydrophiliccomponent. The biocompatible polymer also can be a blend of thehydrophobic polymer and the hydrophilic polymer or the polymer having atleast one hydrophilic component, optionally with a biobeneficialmaterial.

The implantable device can be used to prevent, treat, inhibit, delay,reduce, or ameliorate a disorder such as vulnerable plaque, restenosis,stenosis, atherosclerosis, thrombosis, hemorrhage, vascular dissectionor perforation, vascular aneurysm, chronic total occlusion,claudication, anastomotic proliferation for vein and artificial grafts,bile duct obstruction, ureter obstruction, tumor obstruction, otherdiseases associated with lipid plaque formation and a combinationthereof. The device is preferably useful in patient subsets includingtype I and type II diabetics, more particularly, where the disorder isrestenosis, vulnerable plaque and/or progression of atherosclerosis fortype I and type II diabetic patients.

Also provided herein is a method of treating a vascular disorder of apatient, comprising locally administrating HDL, recombinant HDL, HDLm ora combination thereof to a site in need of treatment. In someembodiments, the method is for prevention of lipid plaque formation,reduction in the amount of lipid plaque formed, or delaying theformation of lipid plaque.

DETAILED DESCRIPTION

Provided herein is an implantable device capable of releasing anapolipoprotein. In some embodiments, the implantable device can be,e.g., a stent that includes a coating having an apolipoprotein such asHDL, recombinant HDL, HDLm or a combination thereof for controlledrelease of the apolipoprotein. In some other embodiments, theimplantable device can be a bioabsorbable device (e.g., a bioabsorbablestent) such as that carries or includes the apolipoprotein. Thebioabsorbable device can be made of a biocompatible polymer and/or anabsorbable metal. Bioabsorbable is intended to include biodegradable,bioerodable, bioresorbable and the like. The coating or thebioabsorbable device is capable of providing a release profile, such asfast release, sustained release, intermediate release, or a combinationthereof, of the apolipoprotein. The coating or the bioabsorbable devicemay optionally include a biobeneficial material and/or a bioactiveagent. Some exemplary bioactive agents are paclitaxel, docetaxel,estradiol, nitric oxide donors, super oxide dismutases, super oxidedismutases mimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl(4-amino-TEMPO), tacrolimus, dexamethasone, rapamycin, rapamycinderivatives, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin,ABT-578, clobetasol, prodrugs thereof, co-drugs thereof, and acombination thereof.

The HDL, HDLm, recombinant HDL, and/or optionally one or more additionalagents can be coated onto the device free of a polymer or in combinationwith a biocompatible polymer. The biocompatible polymer can be ahydrophobic polymer, which can be durable or bioabsorbable. Thebiocompatible polymer also can be a biobeneficial material, ahydrophilic polymer or a polymer having at least one hydrophiliccomponent. The biocompatible polymer also can be a blend of thehydrophobic polymer and the hydrophilic polymer or the polymer having atleast one hydrophilic component, optionally with a biobeneficialmaterial.

The implantable device can be used to for prevention, treatment, delay,inhibition, reduction, or amelioration (collectively referred to as“treatment” or “treating” unless specifically indicated otherwise) ofvascular disease, disorder or occlusion, such as vulnerable plaque,restenosis, stenosis, atherosclerosis, thrombosis, or other disordersand diseases associated with lipid plaque formation. The devices canalso be used for the treatment of hemorrhage, vascular dissection orperforation, vascular aneurysm, chronic total occlusion, claudication,anastomotic proliferation for vein and artificial grafts, bile ductobstruction, ureter obstruction, tumor obstruction, and a combinationthereof. The device is preferably useful in patient subsets includingtype I and type II diabetics, more particularly, where the disorder isrestenosis, vulnerable plaque and/or progression of atherosclerosis fortype I and type II diabetic patients.

As used herein, the term “fast release” refers to a substantial release,e.g., about 50% release of the HDL, recombinant HDL and/or HDLm and/orone or more agents within several minutes to several days, for example,with a period ranging from about 1 hour to about 48 hours, from about 2hours to about 24 hours or from about 5 hours to about 10 hours.

As used herein, the term “sustained release” refers to a substantialrelease, e.g., about 50% release of the HDL, recombinant HDL and/or HDLmand/or one or more agents within several days to several years, forexample, with a period ranging from about 5 days to about two years,from about 5 days to about 1 year, from about 10 days to 10 months, orfrom about 1 month to about 6 months.

As used herein, the term “intermediate rate of release” refers to asubstantial release, e.g., about 50% release of the HDL, recombinant HDLand/or HDLm and/or one or more agents within several hours to severaldays, for example, within a period ranging from about 5 hours to about10 days, from about 5 hours to about 2 days, or from about 10 hours toabout 24 hours.

The term “substantial release” refers to a release of about 1% to about100%, about 5% to about 95%, about 10% to about 90%, about 20% to about80%, about 30% to about 70%, about 40% to about 60%, or about 50% of theHDL, recombinant HDL and/or HDLm and/or one or more agents.

The term “apolipoprotein” generally refers to any of HDL, recombinantHDL, HDLm and a combination thereof. In some embodiments, the term“apolipoprotein” is used interchangeably with the term “drug”.

HDL, Recombinant HDL and HDL Mimics

HDL, or alpha lipoprotein, is a subclass of lipoproteins that transportscholesterol in the blood. HDL is composed of a high proportion ofprotein and relatively little cholesterol; high levels are associatedwith decreased risk of coronary heart disease and atherosclerosis.Lipoprotein is a subtype of apolipoproteins, which have a polypeptidemoiety and a non-polypeptide moiety. Lipoprotein is a conjugated proteinhaving a lipid component; the principal means for transporting lipids inthe blood.

There are two major forms of HDL in the bloodstream of any individualhuman. One is AI-HDL (or LpA-I), containing the protein apolipoproteinA-I (apoA-I), and the other is AI/AII-HDL (or LpA-I, A-II), containingboth apoA-I and the protein apolipoprotein A-II (apoA-II).

The functions of the two components of HDL have been extensivelyinvestigated. Studies have shown that there are inverse relationshipsbetween HDL-cholesterol and apo A-I plasma levels and the risk ofcoronary heart disease (CHD). Apo A-II and Lp A-I:A-II plasma levelswere found to be related to apo A-II production rate rather than to apoA-II catabolism. HDL reduces CHD risk by promoting the transfer ofperipheral free cholesterol to the liver through the so-called “reversecholesterol transfer” (See, for example, U.S. Pat. Nos. 5,746,223 and6,367,479 to Williams). Recent studies suggested that apo A-II is not astrong determinant of lipid metabolism, but is rather a modulator ofreverse cholesterol transport (see, Tailleux, et al., Atherosclerosis164(1):1-13 (2002)).

As used herein, in one embodiment, the term HDL encompasses any naturalapolipoproteins that include a polypeptide moiety and a non-polypeptidemoiety. For example, the apolipoproteins can include apoA-I, apoA-II,AI/AII-HDL, or a mixture thereof that complexes with a non-polypeptidemoiety which can be a phospholipid such as cholesterol.

In another embodiment, the HDL can be recombinant apolipoproteins thatmay include any recombinant apoA-I, apoA-II, AI/AII-HDL, or a mixturethereof that complexes with a non-polypeptide moiety which can be aphospholipid such as cholesterol. The recombinant HDL can be expressedin any organism such as transgenic animal, transgenic plant, ortransgenic bacteria. Some representative recombinant HDLs or componentsthereof are described in, for example, Chiesa, et al., Ann Med.35(4):267-73 (2003); Hu, et al., Yi Chuan Xue Bao. 30(1):20-4 (2003);Chiesa, Curr Opin Lipidol. 14(2):159-63 (2003); Chroni, et al., J BiolChem. 28;278(9):6719-30 (2003); Tian, et al., Biochim Biophys Acta.1599(1-2):56-64 (2002); Gorshkova, et al., Biochemistry 41(33):10529-39(2002); and Panagotopulos, et al., Protein Expr Purif. 25(2):353-61(2002)).

Also useful for coating the implantable device described herein aresynthetic HDLs or HDL mimics capable of carrying cholesterol away fromthe arteries and back to the liver. In one embodiment, the term HDLmincludes either a synthetic HDL or HDL mimics that has a polypeptidemoiety that mimics the structure and/or function of any domain ofapoA-I, apoA-II, AI/AII-HDL or a phospholipid moiety. Synthetic HDLs andHDLms are well documented in the art. For example, the HDLm can beETC-642, which is a complex of a 22-amino acid peptide and phospholipidsthat mimics the functions of HDL. The peptide component of ETC-642mimics the biological properties of apolipoproteinA-I, the major proteinin HDL, to promote removal of excess cholesterol and other lipids fromartery walls and other tissues and enhance reverse lipid transport (See,for example, “Single-dose Intravenous Infusion of ETC-642, a 22-merApoA-I Analogue and Phospholipids Complex, Elevates HDL-C inAtherosclerosis Patients,” American Heart Association ScientificSessions, Nov. 11, 2003, Orlando, Fla.). Other useful HDLms arecholesterol acceptor compounds such as large unilamellar vesicles orsmall unilamellar vesicles described in, for example, U.S. Pat. Nos.5,746,223, 5,858,400; 5,948,435; 6,079,416 and 6,367,479 to Williams.Other representative useful HDLms may also include Apo A-I and/or ApoA-II agonists or modulators described in U.S. Pat. Nos. 6,602,854;6,585,995; 6,573,239; 6,518,412; 6,376,464; 6,265,377; 6,156,727;6,046,166; and 6,037,323.

In one embodiment, an implantable device such as a stent can be coatedwith a coating that includes HDL, recombinant HDL, HDLm, or acombination thereof to delivery any of these apolipoprotein species.Implanted stents have been used to carry medicinal agents, such asthrombolytic agents. U.S. Pat. No. 5,163,952 to Froix discloses athermal memoried expanding plastic stent device formulated to carry amedicinal agent in the material of the stent itself. Pinchuk, in U.S.Pat. No. 5,092,877, discloses a stent of a polymeric material which mayhave a coating associated with the delivery of drugs. Other patentswhich are directed to devices of the class utilizing bio-degradable orbio-sorbable polymers include Tang et al., U.S. Pat. No. 4,916,193, andMacGregor, U.S. Pat. No. 4,994,071.

The coating may optionally include one or more additional bioactiveagent such as a phospholipid. The phospholipid includes, for example,phosphoryl choline, phosphoryl serine, phosphoryl inositol,di-phosphoryl glycerol, zwitterions ion phosphoryl ethanolamine, etc,and a combination thereof. The composition can be used to form a coatingon an implantable device such as a drug-delivery stent.

In a further aspect of the present invention, any of the apolipoproteinscan be carried or included in a durable, biodegradable or bioabsorbablemedical device, e.g., a stent.

In another embodiment, HDL, recombinant HDL, and HDLm can be deliveredlocally without a polymer carrier, such as through an implantable pumpor through coating the apolipoprotein directly on the implantabledevices such as a stent. Implantable pump has been successfully used incontrolled, local delivery of diagnostic and therapeutic agents (see,e.g., Perry, C. R., et al., Clin Orthop. 226:222-30 (1988); Bret Berner,Steven M. Dinh, Electronically Controlled Drug Delivery, CRC Press,1998).

Coating Constructs

The HDL, recombinant HDL, HDLm, and optionally one or more additionalbioactive agents other than HDL, recombinant HDL, and HDLm, and any ofthe polymers described herein can be made into different coatingconstructs to provide various release profile of the HDL, recombinantHDL and/or HDLm and optionally one or more bioactive agents other thanthe HDL and HDLm.

In one aspect of the present invention, the coating construct comprisesa layer of the HDL, recombinant HDL and/or HDLm and optionally one ormore bioactive agents and a topcoat comprising a polymer or polymerblend. The polymer can be a hydrophobic biocompatible polymer, ahydrophilic biocompatible polymer, or a biocompatible polymer thatincludes a hydrophilic component. The hydrophilic polymer topcoat can bea bioresorbable or a durable hydrogel or a biocompatible coating definedherein. In a further embodiment, the polymer is a blend of any of thehydrophobic biocompatible polymer, hydrophilic biocompatible polymer orthe biocompatible polymer that includes a hydrophilic component.

In some embodiments, the coating construct comprises a polymericreservoir layer that includes the HDL, recombinant HDL and/or HDLm andoptionally one or more bioactive agents. The polymer can be ahydrophobic biocompatible polymer, a hydrophilic biocompatible polymer,or a biocompatible polymer that includes a hydrophilic component. In afurther embodiment, the polymer is a blend of any of the hydrophobicbiocompatible polymer, hydrophilic biocompatible polymer or thebiocompatible polymer that includes a hydrophilic component.

In a further aspect of the present invention, the coating constructcomprises two or more reservoir layers that include the HDL, recombinantHDL and/or HDLm and optionally one or more bioactive agents, and apolymer or a polymer blend. The polymer can be a hydrophobicbiocompatible polymer, a hydrophilic biocompatible polymer, or abiocompatible polymer that includes a hydrophilic component. In afurther embodiment, the polymer is a blend of any of the hydrophobicbiocompatible polymer, hydrophilic biocompatible polymer or thebiocompatible polymer that includes a hydrophilic component.

The coating construct can be multiple layers, such as a primer layer, areservoir layer including the drug(s) and a topcoat layer. The reservoirlayer can include sublayers of the same drug or different drugs. Thereservoir layer can be with or without polymer(s).

The coating constructs described herein can provide a controlled releaseof the HDL, recombinant HDL and/or HDLm and optionally one or morebioactive agents. When a fast release of the HDL, recombinant HDL and/orHDLm and/or one or more agents is desirable, a hydrophilic biocompatibleor a biocompatible polymer including a hydrophilic component can be usedto form a reservoir layer with relatively high drug-to-polymer ratio ora topcoat layer. Alternatively, the bioactive agents can be applieddirectly on the device without carrier polymer with or without a topcoatpolymer. When a sustained release of the HDL, recombinant HDL and/orHDLm and/or one or more agents is desirable, a relatively hydrophobicbiocompatible polymer can be used to form a reservoir layer or a topcoatlayer. Alternatively a hydrophilic polymer can be used with relativelylow drug-to-polymer ratio. When a bioresorbable polymer is used as acarrier, the drug release could be two phases, with a first phase ofdrug release through diffusion via percolation channel and with thesecond phase of drug release through polymer degradation and drugdissolution. If an intermediate release rate of the HDL, recombinant HDLand/or HDLm and/or one or more agents is desirable, a polymer blend ofany of the hydrophobic biocompatible polymer, hydrophilic biocompatiblepolymer or the biocompatible polymer that includes a hydrophiliccomponent can be used. The ratio of the hydrophilic polymer and/or thepolymer containing a hydrophilic component to the hydrophobicbiocompatible polymer can be varied to achieve a desired rate ofrelease. If apolipoprotein is lipophilic, the drug can be applieddirectly on the device with or without a durable or bioresorbablepolymer topcoat to achieve intermediate release profile. A coatingconstruct with multiple drug reservoir layers can be used to achieve acombination of a fast release with a sustained release of the HDL,recombinant HDL and/or HDLm and/or one or more agents.

In one embodiment, the device includes a coating that comprises a HDL,recombinant HDL and/or HDLm and a hydrophobic biocompatible polymer. Thebiocompatible polymer can provide a controlled release of a bioactiveagent, if included in the coating and/or if bound to a substrate, whichcan be the surface of an implantable device or a coating thereon.Controlled release and delivery of bioactive agent using a polymericcarrier has been extensively researched in the past several decades(see, for example, Mathiowitz, Ed., Encyclopedia of Controlled DrugDelivery, C.H.I.P.S., 1999). For example, poly(lactic acid) (PLA) baseddrug delivery systems have provided controlled release of manytherapeutic drugs with various degrees of success (see, for example,U.S. Pat. No. 5,861,387 to Labrie, et al.). The release rate of thebioactive agent can be controlled by, for example, selection of aparticular type of biocompatible polymer, which can provide a desiredrelease profile of the bioactive agent. The release profile of thebioactive agent can be further controlled by selecting the molecularweight of the biocompatible polymer, the ratio of the biocompatiblepolymer to the bioactive agent, and the degradation rate ofbioresorbable polymer carrier and/or topcoat. Additional ways to controlthe release of the bioactive agent are, for example, specific design ofthe polymer coating construct, conjugating the active agent onto thepolymeric backbone, designing a micro-phase separated polymer thatincludes rigid and mobile segments where the active resides in the moremobile segment, and designing a polymer in which the bioactive has anappropriate level of solubility. One of ordinary skill in the art canreadily select a carrier system using a biocompatible polymer to providea controlled release of the bioactive agent. Examples of the controlledrelease carrier system can come from the examples provided above;however, other possibilities not provided are also achievable.

In some embodiments, the device provides a controlled or sustainedrelease of the HDL, recombinant HDL and/or HDLm over a period rangingfrom, for example, several days to several months or years.

Biocompatible Polymers

The biocompatible polymer that can be used with the HDL, recombinant HDLor HDLm in the coatings or medical devices described herein can be anybiocompatible polymer known in the art, which can be biodegradable ornondegradable and can be hydrophobic or hydrophilic. Representativeexamples of polymers that can be used to coat an implantable device inaccordance with the present invention include, but are not limited to,poly(ester amide), ethylene vinyl alcohol copolymer (commonly known bythe generic name EVOH or by the trade name EVAL), poly(hydroxyvalerate),poly(L-lactic acid), poly(L-lactide), poly(D,L-lactide),poly(L-lactide-co-D,L-lactide), polycaprolactone,poly(lactide-co-glycolide), poly(hydroxybutyrate),poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester,polyanhydride, poly(glycolic acid), poly(D,L-lactic acid),poly(D,L-lactide-co-glycolide) (PDLLAGA), poly(glycolicacid-co-trimethylene carbonate), polyphosphoester, polyphosphoesterurethane, poly(amino acids), polycyanoacrylates, poly(trimethylenecarbonate), poly(iminocarbonate), poly(butyleneterephthalate-co-poly((ethylene glycol) (PEG)-terephthalate),polyurethanes, polyphosphazenes, silicones, polyesters, polyolefins,polyisobutylene and ethylene-alphaolefin copolymers, acrylic polymersand copolymers, vinyl halide polymers and copolymers, such as polyvinylchloride, polyvinyl ethers, such as polyvinyl methyl ether,polyvinylidene halides such as vinylidene fluoride based homo orcopolymer under the trade name Solef™ or Kynar™, for example,polyvinylidene fluoride (PVDF) orpoly(vinylidene-co-hexafluoropropylene) (PVDF-co-HFP) and polyvinylidenechloride, polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics suchas polystyrene, polyvinyl esters, such as polyvinyl acetate, copolymersof vinyl monomers with each other and olefins such as ethylene-methylmethacrylate copolymers, acrylonitrile-styrene copolymers, ABS resins,and ethylene-vinyl acetate copolymers, polyamides such as Nylon 66 andpolycaprolactam, alkyd resins, polycarbonates, polyoxymethylenes,polyimides, polyethers, poly(glyceryl sebacate), polypropylenefumarate), epoxy resins, polyurethanes, rayon, rayon-triacetate,cellulose acetate, cellulose butyrate, cellulose acetate butyrate,cellophane, cellulose nitrate, cellulose propionate, cellulose ethers,and carboxymethyl cellulose.

A preferred biocompatible, hydrophobic polymer is a polyester, such asone of poly(D,L-lactic acid) (PDLLA), poly(L-lactic acid) (PLLA),poly(D-lactic acid) (PDLA), poly(D,L-lactic acid-co-glycolic acid)(PDLLGA), poly(glycolic acid) (PGA), polyhydroxyalkanoates (PHA),poly(3-hydroxybutyrate) (PHB),poly(3-hydroxybutyrate-co-3-hydroxyvalerate), poly((3-hydroxyvalerate),poly(3-hydroxyhexanoate), poly(4-hydroxybutyrate),poly(4-hydroxyvalerate), poly(4-hydroxyhexanoate), polycaprolactone(PCL), and a combination thereof.

The biobeneficial material that can be used with the HDL or HDLm to formthe coatings or medical devices described herein can be a polymericmaterial or non-polymeric material. The biobeneficial material ispreferably flexible and biocompatible and/or biodegradable (a term whichincludes bioerodable, biodegradable and bioabsorbable), more preferablynon-toxic, non-antigenic and non-immunogenic. A biobeneficial materialis one which enhances the biocompatibility of a device by beingnon-fouling, hemocompatible, actively non-thrombogenic, oranti-inflammatory, all without depending on the release of apharmaceutically active agent.

Representative biobeneficial materials include, but are not limited to,polyethers such as poly(ethylene glycol), copoly(ether-esters) (e.g.PEO/PLA); polyalkylene oxides such as poly(ethylene oxide),polypropylene oxide), poly(ether ester), polyalkylene oxalates,polyphosphazenes, phosphoryl choline, choline, poly(aspirin), polymersand co-polymers of hydroxyl bearing monomers such as hydroxyethylmethacrylate (HEMA), hydroxypropyl methacrylate (HPMA),hydroxypropylmethacrylamide, poly (ethylene glycol) acrylate (PEGA), PEGmethacrylate, 2-methacryloyloxyethylphosphorylcholine (MPC) and n-vinylpyrrolidone (VP), carboxylic acid bearing monomers such as methacrylicacid (MA), acrylic acid (AA), alkoxymethacrylate, alkoxyacrylate, and3-trimethylsilylpropyl methacrylate (TMSPMA),poly(styrene-isoprene-styrene)-PEG (SIS-PEG), polystyrene-PEG,polyisobutylene-PEG, polycaprolactone-PEG (PCL-PEG), PLA-PEG,poly(methyl methacrylate)-PEG (PMMA-PEG), polydimethylsiloxane-co-PEG(PDMS-PEG), poly(vinylidene fluoride)-PEG (PVDF-PEG), PLURONIC™surfactants (polypropylene oxide-co-polyethylene glycol),poly(tetramethylene glycol), hydroxy functional poly(vinyl pyrrolidone),biomolecules such as fibrin, fibrinogen, cellulose, starch, collagen,dextran, dextrin, hyaluronic acid, fragments and derivatives ofhyaluronic acid, heparin, fragments and derivatives of heparin,glycosamino glycan (GAG), GAG derivatives, polysaccharide, elastin,chitosan, alginate, silicones, and a combination thereof. In someembodiments, the polymer can exclude any one of the aforementionedpolymers.

In a preferred embodiment, the biobeneficial material is a blockcopolymer having flexible poly(ethylene glycol) and poly(butyleneterephthalate) blocks (PEGT/PBT) (e.g., PolyActive™). PolyActive™ isintended to include AB, ABA, BAB copolymers having such segments of PEGand PBT (e.g., poly(ethyleneglycol)-block-poly(butyleneterephthalate)-block poly(ethylene glycol)(PEG-PBT-PEG).

Representative hydrophilic materials that can be used includehyaluronate, heparin, polyethylene glycol, polyalkene oxides, blockcopolymer poly(ethylene glycol terephtalate)/poly(butylenesterephtalate) (PEGT/PBT) (PolyActive™) phosphoryl choline,poly(aspirin), poly (N-vinylpyrrolidone) (PNVP), SIS-PEG,polystyrene-PEG, polyisobutylene-PEG, PCL-PEG, PLA-PEG, PMMA-PEG,PDMS-PEG, PVDF-PEG, SIS-hyaluronic acid (HA), polystyrene-HA,polyisobutylene-HA, PCL-HA, PLA-HA, PMMA-HA, PVDF-HA, SIS-heparin,polystyrene-heparin, polyisobutylene-heparin, PCL-heparin, PLA-heparin,PMMA-heparin, PVDF-heparin, and a combination thereof.

Bioactive Agents

Bioactive agents that can be used with HDL, recombinant HDL, and/or HDLmcan be any agent which is a therapeutic, prophylactic, or diagnosticagent. These agents can have anti-proliferative or anti-inflammatoryproperties or can have other properties such as antineoplastic,antiplatelet, anti-coagulant, anti-fibrin, antithrombonic, antimitotic,antibiotic, antiallergic, antioxidant as well as cystostatic agents.Examples of suitable therapeutic and prophylactic agents includesynthetic inorganic and organic compounds, proteins and peptides,polysaccharides and other sugars, lipids, and DNA and RNA nucleic acidsequences having therapeutic, prophylactic or diagnostic activities.Nucleic acid sequences include genes, antisense molecules which bind tocomplementary DNA to inhibit transcription, and ribozymes. Some otherexamples of other bioactive agents include antibodies, receptor ligands,enzymes, adhesion peptides, blood clotting factors, inhibitors or clotdissolving agents such as streptokinase and tissue plasminogenactivator, antigens for immunization, hormones and growth factors,oligonucleotides such as antisense oligonucleotides and ribozymes andretroviral vectors for use in gene therapy. Examples ofanti-proliferative agents include rapamycin and its functional orstructural derivatives, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus),and its functional or structural derivatives, paclitaxel and itsfunctional and structural derivatives. Examples of rapamycin derivativesinclude methyl rapamycin (ABT-578), 40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin.Examples of paclitaxel derivatives include docetaxel. Examples ofantineoplastics and/or antimitotics include methotrexate, azathioprine,vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (e.g.Adriamycin® from Pharmacia & Upjohn, Peapack N.J.), and mitomycin (e.g.Mutamycin® from Bristol-Myers Squibb Co., Stamford, Conn.). Examples ofsuch antiplatelets, anticoagulants, antifibrin, and antithrombinsinclude sodium heparin, low molecular weight heparins, heparinoids,hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclinanalogues, dextran, D-phe-pro-arg-chloromethylketone (syntheticantithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membranereceptor antagonist antibody, recombinant hirudin, thrombin inhibitorssuch as ANGIOMAX™ (bivalirudin, Biogen, Inc., Cambridge, Mass.), calciumchannel blockers (such as nifedipine), colchicine, fibroblast growthfactor (FGF) antagonists, fish oil (omega 3-fatty acid), histamineantagonists, lovastatin (an inhibitor of HMG-CoA reductase, acholesterol lowering drug, brand name Mevacor® from Merck & Co., Inc.,Whitehouse Station, N.J.), monoclonal antibodies (such as those specificfor Platelet-Derived Growth Factor (PDGF) receptors), nitroprusside,phosphodiesterase inhibitors, prostaglandin inhibitors, suramin,serotonin blockers, steroids, thioprotease inhibitors,triazolopyrimidine (a PDGF antagonist), nitric oxide or nitric oxidedonors, super oxide dismutases, super oxide dismutase mimetic,4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), estradiol,anticancer agents, dietary supplements such as various vitamins, and acombination thereof. Examples of anti-inflammatory agents includingsteroidal and non-steroidal anti-inflammatory agents include tacrolimus,dexamethasone, clobetasol, and a combination thereof. Examples of suchcytostatic substance include angiopeptin, angiotensin converting enzymeinhibitors such as captopril (e.g. Capoten® and Capozide® fromBristol-Myers Squibb Co., Stamford, Conn.), cilazapril or lisinopril(e.g. Prinivil® and Prinzide® from Merck & Co., Inc., WhitehouseStation, N.J.). An example of an antiallergic agent is permirolastpotassium. Other therapeutic substances or agents which may beappropriate include alpha-interferon, bioactive RGD, and geneticallyengineered epithelial cells. The foregoing substances can also be usedin the form of prodrugs or co-drugs thereof. The foregoing substancesare listed by way of example and are not meant to be limiting. Otheractive agents which are currently available or that may be developed inthe future are equally applicable.

The dosage or concentration of the agent required to produce a favorabletherapeutic effect should be less than the level at which the agentproduces toxic effects and greater than the level at whichnon-therapeutic results are obtained. The dosage or concentration of theagent required can depend upon factors such as the particularcircumstances of the patient, the nature of the tissues being deliveredto, the nature of the therapy desired, the time over which theingredient administered resides at the vascular site, and if otheragents are employed, the nature and type of the substance or combinationof substances. Therapeutic effective dosages can be determinedempirically, for example by infusing vessels from suitable animal modelsystems and using immunohistochemical, fluorescent or electronmicroscopy methods to detect the agent and its effects, or by conductingsuitable in vitro studies. Standard pharmacological test procedures todetermine dosages are understood by one of ordinary skill in the art.

Examples of Implantable Device

As used herein, an implantable device may be any suitable medicalsubstrate that can be implanted in a human or veterinary patient.Examples of such implantable devices include self-expandable stents,balloon-expandable stents, stent-grafts, grafts (e.g., aortic grafts),artificial heart valves, cerebrospinal fluid shunts, pacemakerelectrodes, endocardial leads (e.g., FINELINE® and ENDOTAK®, availablefrom Guidant Corporation, Santa Clara, Calif.), and implantable pump.The underlying structure of the device can be of virtually any design.The device can be made of a metallic material or an alloy such as, butnot limited to, cobalt chromium alloy (ELGILOY®), stainless steel(316L), high nitrogen stainless steel, e.g., BIODUR®, cobalt chromealloy L-605, “MP35N,” “MP20N,” ELASTINITE® (Nitinol), tantalum,nickel-titanium alloy, platinum-iridium alloy, gold, magnesium, or acombination thereof “MP35N” and “MP20N” are trade names for alloys ofcobalt, nickel, chromium and molybdenum available from Standard PressSteel Co., Jenkintown, Pa. “MP35N” consists of 35% cobalt, 35% nickel,20% chromium, and 10% molybdenum. “MP20N” consists of 50% cobalt, 20%nickel, 20% chromium, and 10% molybdenum. Devices made frombioabsorbable or biostable polymers could also be used with theembodiments of the present invention. In some embodiments, abioabsorbable or bioerodable stent is used to carry HDL, recombinant HDLor HDLm.

Method of Use

In accordance with embodiments of the invention, a coating of thevarious described embodiments can be formed on an implantable device orprosthesis, e.g., a stent. For coatings including one or more activeagents, the agent will retain on the medical device such as a stentduring delivery and expansion of the device, and released at a desiredrate and for a predetermined duration of time at the site ofimplantation. Preferably, the medical device is a stent. A stent havingthe above-described coating is particularly useful for treating occludedregions of blood vessels caused by atherosclerosis, abnormal orinappropriate migration and proliferation of smooth muscle cells,thrombosis, and restenosis. Stents may be placed in a wide array ofblood vessels, both arteries and veins.

For implantation of a stent, an angiogram is first performed todetermine the appropriate positioning for stent therapy. An angiogram istypically accomplished by injecting a radiopaque contrasting agentthrough a catheter inserted into an artery or vein as an x-ray is taken.A guidewire is then advanced through the lesion or proposed site oftreatment. Over the guidewire is passed a delivery catheter which allowsa stent in its collapsed configuration to be inserted into thepassageway. The delivery catheter is inserted either percutaneously orby surgery into the femoral artery, brachial artery, femoral vein, orbrachial vein, and advanced into the appropriate blood vessel bysteering the catheter through the vascular system under fluoroscopicguidance. A stent having the above-described coating may then beexpanded at the desired area of treatment. A post-insertion angiogrammay also be utilized to confirm appropriate positioning.

Embodiments of Alternative Methods of Treatment

As indicated before, HDL, recombinant HDL, HDLm and optionally one ormore agents can be delivered locally by means other than a stent. Insome embodiments, delivery can be systemic. The therapy can beexclusively a non-stent therapy. In some embodiments, HDL, recombinantHDL or HDLm can be delivered locally and/or systemically, in conjecturewith stent therapy. The stent can be a bare metal stent, a drug deliverystent, or a bioabsorbable stent. Local or systemic delivery can bebefore, during and/or subsequent to the implantation of the stent. Insome embodiments, a drug eluting stent can be implanted (for examplecarrying everolimus, ABT-578™, paclitaxel, docetaxel, paclitaxelderivatives, or rapamycin) and prior to, during and/or subsequent to theimplantation of the drug eluting stent, HDL, recombinant HDL or HDLm canbe delivered via a catheter or a porous balloon system. Drug deliveryvia catheters or balloon systems is known to one having ordinary skillin the art.

For various modes of local or systemic delivery, HDL, recombinant HDL orHDLm can be formulated with a pharmaceutical carrier of solid or liquidform. A solid carrier can include one or more substances which may actas flavoring agents, lubricants, solubilizers, suspending agents,fillers, glidants, compression aids, binders or tablet-disintegratingagents. Additionally, the solid carrier can be an encapsulatingmaterial. In powder, the carrier can be a finely divided solid. Intablets, HDL, recombinant HDL or HDLm (and optionally one or moreadditional agents) is mixed with a carrier having the necessarycompression properties in suitable proportions and compacted in theshape and size desired. The powder and tablets can contain up to about99% of the active component. Suitable solid carriers include, forexample, calcium phosphate, magnesium stearate, talc, sugars, lactose,dexyin, starch, gelatin, cellulose, methyl cellulose, sodiumcarboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ionexchange resins.

Liquid carriers are used in preparing solutions, suspensions, emulsions,syrups, elixirs and pressurized compositions. HDL, recombinant HDL orHDLm (and optionally one or more additional agents) can be dissolved orsuspended in a pharmaceutically acceptable liquid carrier such as wateror suitable organic solvents. The liquid carrier can contain othersuitable pharmaceutical additives such as solubilizers, emulsifiers,buffers, preservatives, sweeteners, flavoring agents, suspending agents,thickening agents, colors, viscosity regulators, stabilizers orosmo-regulators. Suitable examples of liquid carrier for oral andparenteral administration include water, sucrose solution, lipidformulations, phosphate buffered saline solution, alcohols such asmonohydric and polyhydric alcohols, and emulsions such as theoil-in-water or water-in-oil type. For parenteral administration, thecarrier can also be an oily ester such as ethyl oleate and isopropylmyristate. The liquid carrier for pressurized compositions can be, forexample, a halogenated hydrocarbon.

In some embodiments, systemic administration of HDL, recombinant HDL orHDLm (and optionally one or more additional agents) can be accomplishedorally or parenterally including intravascularly, rectally,intranasally, intrabronchially, or transdermally. Liquid carriers whichare sterile solutions or suspensions can be injected intramuscularly,intraperitoneally, subcutaneously, and intravenously. Rectaladministration can be in the form of conventional suppository. Foradministration by intranasal or intrabronchial inhalation orinsufflation, HDL, recombinant HDL or HDLm (and optionally one or moreadditional agents) can be formulated into an aqueous or partiallyaqueous solution, which can then be utilized in the form of an aerosol.HDL, recombinant HDL or HDLm (and optionally one or more additionalagents) can be administered transdermally through the use of atransdermal patch and a carrier that is inert to and mutually compatiblewith the active component)s), is non-toxic to the skin, and allows forthe delivery of the active component(s) for systemic absorption into theblood stream via the skin. Again, this treatment can be conjunction withstent therapy. The treatment can be initiated in advance of stentimplantation, generally simultaneously or subsequent to the stent beingimplanted in the body. The carrier may take any number of forms such ascreams, ointments, pastes, and gels. The creams and ointments may beviscous liquids or semisolid emulsions of either the oil-in-water orwater-in-oil type. Pastes made of absorptive powders dispersed inpetroleum or hydrophilic petroleum containing the active component mayalso be suitable. Other devices capable of releasing HDL, recombinantHDL or HDLm (and optionally one or more additional agents) into theblood stream include semi-permeable membranes covering a reservoircontaining the active component, with or without a carrier.

In some embodiments, local administration can be accomplished by avariety of techniques which administer HDL, recombinant HDL or HDLm (andoptionally one or more additional agents) at or near the target site.The following examples of local delivery techniques are provided forillustrative purposes and are not intended to be limiting. Examplesinclude local delivery catheters, site specific carriers, non-stentimplants, direct application, or direct injection. Local delivery by acatheter allows for the administration directly to a targeted lesion.Local delivery by site specific carriers is conducted by attaching HDL,recombinant HDL or HDLm to a carrier which will direct or link the drugto targeted cells. Examples of this delivery technique include the useof carrier such as a protein ligand, a monoclonal antibody or a membraneanchored linker.

Local delivery by a non-stent implant is the placement of a matrixcarrying HDL, recombinant HDL or HDLm (optionally with other drugs) atthe target site. The matrix can release HDL, recombinant HDL or HDLmcomponent via, for example, diffusion, degradation, chemical reaction,solvent activators, etc. One example of local delivery by an implant caninclude direct injection of vesicles or micro-particles into the targetsite. These micro-particles may be composed of substances such asproteins, lipids, carbohydrates or synthetic polymers. Themicro-particles can have HDL, recombinant HDL or HDLm impregnatedtherein and/or coated thereon.

Yet in another example, a delivery system is provided in which a polymerthat contains HDL, recombinant HDL or HDLm (and optionally other agents)is injected into the lesion in liquid form. The polymer can then becured to form the implant in situ. In situ polymerization can beaccomplished by photocuring or chemical reaction. Photocuring isconducted by mixing a polymer such as, but not limited to, acrylate ordiacrylate modified polyethylene glycol (PEG), PLURONIC®, polybutyleneteraphthalate-co-polyethylene oxide, polyvinyl alcohol, hydroxy ethylmethacrylate (HEMA), hydroxy ethyl methacrylate-co-polyvinylpyrrolidone, HEMA-co-PEG, or glycidol acrylate modified Heparin orsulfated dextran with the active component, with or without aphotosensitizer (e.g., benzophenone) or a photoinitiator (e.g., 2,2dimethoxy 2-phenyl acetophenone, and eosin-Y). The precursor system canbe activated by a suitable wavelength of light corresponding to thesystem. The activation will result in a cured system that incorporatesHDL, recombinant HDL or HDLm. Chemical reaction can be conducted byincorporating di-isocyanate, aldehyde, N-hydroxy succinimide,di-imidazole, —NH2, —COOH, with a polymer such as PEG or HEMA. Theprocess of photocuring and chemical reaction is known to one of ordinaryskill in the art.

Application via implants is not limited to the above described routesand other techniques such as grafts, micropumps or application of afibrin glue or hydrogel containing HDL, recombinant HDL or HDLm aroundthe exterior of a designated region of the adventitia can also beimplemented by one of ordinary skill in the art.

In some embodiments, local delivery by direct application includes theuse of topical applications. An example of a local delivery by directapplication is applying the HDL, recombinant HDL or HDLm (optionallywith other agents) directly to the arterial bypass graft during thesurgical procedure. Another example of local delivery by directapplication includes delivery of the HDL, recombinant HDL or HDLm intothe pericardial sac as is known by one of ordinary skill in the art.

Local delivery by direct injection includes injecting a liquid carriercontaining HDL, recombinant HDL or HDLm (optionally with other agents)directly into the proliferative or target site. The liquid carriershould be inert to and mutually compatible with HDL, recombinant HDL orHDLm. The component can be in true solution or suspended in fineparticles in the carrier. A suitable example of an inert carrierincludes a sterile saline solution.

Systemic or local administration via the various disclosed routes may becontinuous, intermittent, applied in a single treatment or multipletreatments. For example a regiment can be contemplated which involves asingle dose given before and/or at the time of the treatment procedure,e.g., balloon or stent therapy, and with a follow-up dose deliveredafter a predetermined time period subsequent to the treatment procedure.

One of the aforementioned bioactive or therapeutic agents, e.g.,everolimus, ABT-578™, paclitaxel, docetaxel, paclitaxel derivatives, orrapamycin can also be administrated prior to, contemporaneously with, orsubsequent to the administration of HDL, recombinant HDL or HDLm. Thiscan be accomplished via the same route or via mixed routes. For example,a vascular stent can be impregnated with everolimus and HDL, recombinantHDL or HDLm can be administered orally o prior to the implantationprocedure and/or contemporaneously via a catheter.

Local, including via a stent, and systemic application of HDL,recombinant HDL or HDLm is particularly useful for prevention,treatment, delay, inhibition, reduction, or amelioration (collectivelyreferred to as “treatment” or “treating” unless specifically indicatedotherwise) of vascular disease, disorder or occlusion, such asvulnerable plaque, restenosis, stenosis, atherosclerosis, thrombosis, aswell as other disorders associated with lipid plaque formation. In someembodiments, local (e.g., via stent) and systemic application is forprevention of lipid plaque formation, reduction in the amount of lipidplaque formed, or delaying the formation of lipid plaque.

The embodiments of the invention are also useful for hemorrhage,vascular dissection or perforation, vascular aneurysm, chronic totalocclusion, claudication, anastomotic proliferation for vein andartificial grafts, bile duct obstruction, ureter obstruction, tumorobstruction, and a combination thereof.

The device is preferably useful in patient subsets including type I andtype II diabetics, more particularly, where the disorder is restenosis,vulnerable plaque and/or progression of atherosclerosis for type I andtype II diabetic patients.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the appended claims are toencompass within their scope all such changes and modifications as fallwithin the true spirit and scope of this invention.

What is claimed is:
 1. A method of treating a human being in need oftreatment of a medical condition, comprising implanting in the humanbeing an implantable medical device comprising a coating comprising ahydrophobic polymer and a biobeneficial material, and the coating alsocomprising a high-density lipoprotein (HDL), a recombinant HDL, or acombination thereof, wherein the hydrophobic polymer is a polyesterselected from the group consisting of poly(D, L-lactic acid) (PDLLA),poly(L-lactic acid) (PLLA), poly(D-lactic acid) (PDLA), poly(D, L-lacticacid-co-glycolic acid) (PDLLGA), poly(glycolic acid) (PGA),polyhydroxyalkanoates (PHA), poly(3-hydroxybutyrate) (PHB),poly(3-hydroxybutyrate-co-3-hydroxyvalcrate), poly(3-hydroxyvalerate),poly(3-hydroxyhexanoate), poly(4-hydroxybutyrate),poly(4-hydroxyvalerate), poly(4-hydroxyhexanoate), polycaprolactone(PCL), and combinations thereof; wherein the implantable medical devicecomprises a stent suitable for use in a blood vessel; wherein thebiobeneficial material is a block copolymer having flexiblepoly(ethylene glycol) and poly(butylene terephthalate) blocks, andwherein the medical condition is selected from the group consisting ofvulnerable plaque, restenosis, stenosis, atherosclerosis, thrombosis,hemorrhage, vascular dissection or perforation, vascular aneurysm,chronic total occlusion, claudication, anastomotic proliferation forvein and artificial grafts, and combinations thereof.
 2. The method ofclaim 1, wherein the implantable medical device further comprises adrug.
 3. The method of claim 2, wherein the drug of the implantablemedical device is everolimus, zotarolimus, paclitaxel, docetaxel,rapamycin, 40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]-ethyl-rapamycin, 40-O-tetrazole-rapamycin, ora combination thereof.
 4. The method of claim 1, wherein the methodadditionally comprises local administration of a high-densitylipoprotein (HDL), a recombinant HDL, a high-density lipoprotein mimic(HDLm), or a combination thereof; systemic delivery of a high-densitylipoprotein (HDL), a recombinant HDL, a high-density lipoprotein mimic(HDLm), or a combination thereof; or both local and systemic delivery ofa high-density lipoprotein (HDL), a recombinant HDL, a high-densitylipoprotein mimic (HDLm), or a combination thereof.
 5. The method ofclaim 1, wherein the human being is a diabetic.
 6. A method of treatinga vascular disorder of a patient, comprising implanting in the patientan implantable medical device comprising a hydrophobic polymer and ahigh-density lipoprotein mimic (HDLm) and a biobeneficial material,wherein the hydrophobic polymer is a polyester selected from the groupconsisting of poly(3-hydroxyhexanoate), poly(4-hydroxyhexanoate), andcombination thereof, wherein the implantable medical device comprises astent suitable for use in a blood vessel, and wherein HDLm comprises apolypeptide moiety that mimics the structure or function of a domain ofapoA-I, apoA-II, or AI/AII-HDL.
 7. The method of claim 6, wherein thevascular disorder is vulnerable plaque, restenosis, stenosis,atherosclerosis, thrombosis, or a combination thereof.
 8. The method ofclaim 6, wherein the method additionally comprises local administrationof a high-density lipoprotein (HDL), a recombinant HDL, a high-densitylipoprotein mimic (HDLm), or a combination thereof.
 9. The method ofclaim 8, wherein the local administration is delivery by a catheter, aporous balloon, or both.
 10. The method of claim 8, wherein the localadministration is delivery by an implantable pump, an implant which isnot a stent, direct injection, local topical administration, or acombination thereof.
 11. The method of claim 6, wherein the patient is adiabetic.
 12. The method of claim 6, wherein the method additionallycomprises systemic delivery of a high-density lipoprotein (HDL), arecombinant HDL, a high-density lipoprotein mimic (HDLm), or acombination thereof.
 13. The method of claim 6, wherein the implantablemedical device further comprises a drug.
 14. The method of claim 13,wherein the drug of the implantable medical device is everolimus,zotarolimus, paclitaxel, docetaxel, rapamycin,40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]-ethyl-rapamycin, 40-O-tetrazole-rapamycin, ora combination thereof.
 15. The method of claim 6, wherein thebiobeneficial material of the coating of the implantable medical deviceis selected from the group consisting of polymers and co-polymers formedof monomer(s) with at least one monomer being selected from the groupconsisting of hydroxyethyl methacrylate (HEMA), hydroxypropylmethacrylate (HPMA), 2-methacryloyloxyethyl-phosphorylcholine (MPC), and3-trimethylsilylpropyl methacrylate (TMSPMA).
 16. An implantable medicaldevice comprising a coating comprising a hydrophobic polymer, and abiobeneficial material, and the coating also comprising a high-densitylipoprotein (HDL), a recombinant HDL, or a combination thereof; whereinthe hydrophobic polymer is a polyester selected from the groupconsisting of poly(D, L-lactic acid) (PDLLA), poly(L-lactic acid)(PLLA), poly(D-lactic acid) (PDLA), poly(D, L-lactic acid-co-glycolicacid) (PDLLGA), poly(glycolic acid) (PGA), polyhydroxyalkanoates (PHA),poly(3-hydroxybutyrate) (PHB),poly(3-hydroxybutyrate-co-3-hydroxyvalerate), poly(3-hydroxyvalerate),poly(3-hydroxyhexanoate), poly(4-hydroxybutyrate),poly(4-hydroxyvalerate), poly(4-hydroxyhexanoate), polycaprolactone(PCL), and combinations thereof; wherein the implantable medical devicecomprises a stent suitable for use in a blood vessel; and wherein thebiobeneficial material is a block copolymer having flexiblepoly(ethylene glycol) and poly(butylene terephthalate) blocks.
 17. Theimplantable medical device of claim 16, wherein the hydrophobic polymerof the coating of the implantable medical device ispoly(3-hydroxyhexanoate), poly(4-hydroxyhexanoate), or a combinationthereof.
 18. The implantable medical device of claim 16, wherein thehydrophobic polymer of the coating of the implantable medical device ispoly(D, L-lactic acid) (PDLLA), poly(L-lactic acid) (PLLA),poly(D-lactic acid) (PDLA), poly(D, L-lactic acid-coglycolic acid)(PDLLGA), poly(glycolic acid) (PGA), polycaprolactone (PCL), or acombination thereof.
 19. The implantable medical device of claim 16,wherein the coating of the implantable medical device comprises ahigh-density lipoprotein (HDL).
 20. The implantable medical device ofclaim 16, wherein the coating of the implantable medical devicecomprises a recombinant HDL.
 21. The implantable medical device of claim16, wherein the implantable medical device comprises a high-densitylipoprotein (HDL), a recombinant HDL, a high-density lipoprotein mimic(HDLm), or a combination thereof incorporated in the body of theimplantable medical device.
 22. The implantable medical device of claim16, wherein the coating of the implantable medical device comprises areservoir region comprising the high-density lipoprotein (HDL), therecombinant HDL, or the combination thereof, and a topcoat region overthe reservoir region.
 23. The implantable medical device of claim 22,wherein the coating of the implantable medical device comprises a primerregion beneath the reservoir region.
 24. The implantable medical deviceof claim 16, wherein the implantable medical device further comprises adrug.
 25. A method of treating a medical condition in a human being,comprising implanting in the human being the implantable medical deviceas defined in claim 24, wherein the medical condition is selected fromthe group consisting of vulnerable plaque, restenosis, stenosis,atherosclerosis, thrombosis, hemorrhage, vascular dissection orperforation, vascular aneurysm, chronic total occlusion, claudication,anastomotic proliferation for vein and artificial grafts, andcombinations thereof.
 26. The method of claim 25, wherein the methodadditionally comprises local administration of a high-densitylipoprotein (HDL), a recombinant HDL, a high-density lipoprotein mimic(HDLm), or a combination thereof; systemic delivery of a high-densitylipoprotein (HDL), a recombinant HDL, a high-density lipoprotein mimic(HDLm), or a combination thereof; or both local delivery of ahigh-density lipoprotein (HDL), a recombinant HDL, a high-densitylipoprotein mimic (HDLm), or a combination thereof, and systemicdelivery of a high-density lipoprotein (HDL), a recombinant HDL, ahigh-density lipoprotein mimic (HDLm), or a combination thereof.
 27. Themethod of claim 25, wherein the drug of the implantable medical deviceis everolimus, zotarolimus, paclitaxel, docetaxel, rapamycin,40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]-ethyl-rapamycin, 40-O-tetrazole-rapamycin, ora combination thereof.
 28. The implantable medical device of claim 16,wherein the coaling of the implantable medical device comprises a drugin addition to the high-density lipoprotein (HDL), the recombinant HDL,or the combination thereof.
 29. The implantable medical device of claim28, wherein the drug of the coating is everolimus, zotarolimus,paclitaxel, docetaxel, rapamycin, or a combination thereof.